We have assembled and analyzed the data from an idiopathic anaphylaxis (IA) patient cohort of 56 individuals studied over FY 2016 and FY2017. This results of this effort were first reported on line in the J Allergy Clin Immunol in 2017. We found that 14% of our study cohort had a monoclonal mast cell disorder that would have been otherwise missed by their clinical presentation. The expression of activation markers by bone marrow mast cells was only seen in patients with a clonal mast cell disorder, which is an important qualifying distinction within the mast cell compartment. Mast cells cultured from patients with anaphylaxis were not hyper-responsive to IgE-mediated degranulation compared to mast cells cultured from healthy donors. Allele-specific qPCR to detect the D816V mutation in KIT was used to create a prediction scoring system to better select patients who would benefit from a bone marrow procedure in order to diagnose clonal mast cell disease. Among a group of 70 patients referred to the NIH (over FY 2016, 2017 and FY 2018) with a diagnosis of IA, six (9%) were found to have IgE to alpha-gal. Upon institution of a diet free of red meat, all six patients had no further episodes of anaphylaxis. This data was published in Allergy in 2018. In FY 2018, we continue to admit patients with IA and antigen-induced anaphylaxis. Most patients are admitted to the inpatient unit and undergo a bone marrow procedure in an attempt to elucidate the etiology and evaluate the pathogenesis of their disease. In collaboration with the NIH Clinical Center's myeloid core facility, we assess all patient bone marrow aspirates and biopsies obtained based on the current WHO criteria to diagnose systemic mastocytosis. Mast cell activation disorders are generally classified into three categories; 1) those associated with mastocytosis and monoclonal mast cell disorders, 2) IgE-mediated mast cell dependent events and 3) idiopathic systemic mast cell degranulation. Our study will examine current consensus models of disease within these groups, as well as emphasize the importance of utilizing historical clues along with laboratory data, such as alpha-gal determination and analysis of the number of alpha tryptase alleles, for a complete evaluation. Omalizumab is approved for the treatment of severe asthma and acts through a mechanism that down regulates the IgE receptor on the surface of basophils, mast cells, and dendritic cells. Omalizumab has been reported to be useful as adjunct therapy in the treatment of diseases other than asthma such as food allergy and chronic urticaria. In FY 2018, we completed patient follow-up for the omalizumab treatment protocol for IA and will report our findings after unblinding of the data for analysis. There have been no serious adverse events attributed to the study drug, in particular drug-induced anaphylaxis. In FY 2018, we analyzed the safety and efficacy of omalizumab over a 12 year period in the treatment of recurrent anaphylaxis in two patients with systemic mastocytosis. We found the drug was well tolerated without adverse events related to administration. In both patients anaphylactic episodes were rare. There was an improvement in cutaneous manifestations in both individuals, along with a significant reduction in serum tryptase and bone marrow mast cell burden in one patient. This report, which is in review, supports the need for long-term controlled trials for the use of omalizumab as a therapeutic option in systemic mastocytosis.